The goal of this NRSA individual postdoctoral fellowship is to facilitate Dr. Sadiya Khan's development as an independent physician-scientist and a leader in translational cardiometabolic research, with a focus on molecular mechanisms of obesity and obesity-related diseases. Dr. Khan and her mentors have designed a specific training plan to build upon her background in internal medicine, clinical cardiology training, and basic and clinical investigation, aiming towards launching her career as an independent investigator. Dr. Khan proposes to develop additional skills during the award period through (1) coursework designed to expand her methodological skills; (2) interaction with a multidisciplinary team of sponsors and collaborators, including those in vascular biology and cardiovascular and genetic epidemiology, and (3) a supervised research project. The overall scientific objective of this project is to investigate the role of plasminogen activator inhibitor-1 (PAI- 1), a serine protease inhibitor, in weight gain and obesity through two primary specific aims: (1) To define the longitudinal profile of circulating PAI-1 levels across early adulthood to middle-age and investigate the association with obesity in the Coronary Artery Disease Risk in Young Adults (CARDIA) study; and (2) To characterize the anthropometric and metabolic phenotype of a unique human PAI-1 loss-of-function cohort in the Berne Amish kindred. The project, along with the proposed coursework and mentorship plan, will allow the candidate to become proficient at translational research methodology with a special emphasis on longitudinal cohort studies, data analysis and management, genetic epidemiology, and scientific writing. This project will meet the mission of the National Institutes of Health by enabling the translation of basic discoveries about the causes of obesity through a collaborative research infrastructure with an overarching goal to help reduce the significant public health burden of obesity and obesity-related diseases. Improving the understanding of the molecular mechanisms underlying the development, progression, and complications of obesity is needed to develop new potential targets for treatment and to aid in primordial and primary prevention efforts. Near the end of the award period, Dr. Khan plans to submit a pathway to independence award application or similar grant using the results of the project to further investigate the molecular mechanisms linking obesity and cardiometabolic disease outcomes.